Impact of Different Surfactants on Oral Bioavailability of Paclitaxel/HPMC-AS Amorphous Solid Dispersion.

Objectives: Surfactants are commonly incorporated into amorphous solid dispersions (ASDs) to improve manufacturing and enhance the dissolution of poorly water-soluble drugs. However, their impact on in vitro dissolution, in vivo bioavailability, and in vitro-in vivo correlation (IVIVC) remains poorly understood, impeding the rational design of ASDs. This study aimed to elucidate the impact of six surfactants: anionic sodium lauroyl glutamate (SLG), sodium taurocholate (NaTC), sodium lauryl sulfate (SLS), and non-ionic polysorbate 80 (TW80), poloxamer 188 (P188), and polyoxyethylene lauryl ether (Brij-35), on the performance of paclitaxel (PTX)/HPMC-AS ASD. Methods: Binary PTX/HPMC-AS and ternary PTX/HPMC-AS/surfactant ASDs were prepared via rotary evaporation for FT-IR study. For dissolution and pharmacokinetic studies, low drug-loading formulations were prepared by physically blending PTX/HPMC-AS ASD with surfactants. Drug-polymer-surfactant interactions were investigated using NMR and FT-IR techniques. Dissolution performance was systematically evaluated by analyzing: (1) solubility of crystalline PTX in HPMC-AS/surfactant solutions; (2) supersaturation sustaining capacity in HPMC-AS/surfactant solutions; (3) surfactant effects on ASD dissolution and supersaturation generation; and (4) phase transformation during ASD dissolution. In vivo bioavailability was assessed in rats. Results: Findings revealed surfactant-specific effects: (1) SLG and P188 minimally affected bioavailability of PTX/HPMC-AS ASD (p > 0.05), consistent with their negligible effect on dissolution, attributable to incompatibility with PTX/HPMC-AS and weak molecular interactions; (2) TW80 significantly reduced bioavailability (p < 0.001) by inducing crystallization; thereby diminishing the amorphous advantage; (3) NaTC, Brij-35, and SLS markedly increased bioavailability (p < 0.001), owing to their compatibility with PTX and HPMC-AS, which enhanced dissolution and maintained amorphous state of precipitates. Surfactants appear to modulate ASD performance by governing supersaturation generation in solution and maintaining amorphous stability in the undissolved solid. Conclusions: The dissolution and bioavailability of ASDs are fundamentally controlled by compatibility between drug, polymer, and surfactant. Surfactant selection critically impacts ASD bioavailability. Comprehensive dissolution characterization, including supersaturation kinetics and precipitate phase analysis, enables prediction of bioavailability. Integrating molecular-level interaction analysis with multidimensional dissolution profiling is therefore essential for rational ASD design.